The present invention relates to a new strategy for the synthesis of [2.2.1]bicyclo nucleosides which is shorter, provides higher overall yields, and thus more cost efficient than previously known methods for synthesis of [2.2.1]bicyclo nucleosides.
Synthesis of the LNA (Locked Nucleic Acid) monomer (1S, 3R, 4R, 7S)-7-hydroxy-1-hydroxymethyl-2,5-dioxabicyclo[2.2.1]heptane uracil was first reported by Obika. (Satashi Obika et al., Tetrahedron Lett.; 1997; 8735-8738) who used a linear strategy based on uridine as starting material for the synthesis of the intermediate 1-(3-O-benzyl-4-C-tosyloxymethyl-xcex2D-ribofuranosyl)uridine. Treatment of the tosylated nucleoside intermediate with sodium hexamethyidisilazide in THF afforded the 2xe2x80x2-O,4xe2x80x2-C-methylene bicyclonucleoside which upon final debenzylation afforded (1S, 3R, 4R, 7S)-7-hydroxy-1-hydroxymethyl-2,5-dioxabicyclo[2.2.1]heptane uracil in 36% yield from the tosylated nucleoside intermediate.
Wengel et al. (Singh, S. K.; Nielsen, P., Koshkin, A. A. and Wengel, J., Chem. Commun., 1998, 455; Koshkin, A. A.; Singh, S. K.; Nielsen, P.; Rajwanshi, V. K.; Kumar, R.; Melgaard, M.; Olsen, C. E. and Wengel, J., Tetrahedron, 1998, 54, 3607) subsequently reported on a convergent strategy for the synthesis of the thymine analogue (1S, 3R, 4R, 7S)-7-hydroxy-1-hydroxymethyl-(thymin-1-yl)-2,5-dioxabicyclo[2.2.1]heptane. Starting from 3-O-benzyl-4-C-hydroxymethyl-1,2-O-isopropylidene-xcex1-D-ribofuranose, the key intermediate for coupling with silylated thymine (or other silylated nucleobases), 4-C-acetoxymethyl-1,2-di-O-acetyl-3,5-di-O-benzyl-D-ribofuranose, was obtained by successive regioselective 5-O-benzylation, acetylation, acetolysis, and another acetylation. Coupling of the key intermediate with silylated thymine afforded the 4xe2x80x2-C-acetoxymethyl nucleoside which upon deacetylation and monotosylation followed by base-induced ring closure, afforded the 2xe2x80x2-O,4xe2x80x2-C-methylene bicyclonucleoside. Final debenzylation gives (1S, 3R, 4R, 7S)-7-hydroxy-1-hydroxymethyl-(thymin-1-yl)-2,5-dioxabicyclo[2.2.1]heptane in 40% yield (calculated from the key intermediate). Analogous synthetic procedure were applied for the synthesis of the uracil, 2-N-isobutyrylguanine, 4-N-benzoylcytosine and 6-N-benzoylcytosine LNA nucleoside analogues. The corresponding 2xe2x80x2-amino-LNA pyrimidine nucleosides were obtained by performing the ring closure in benzylamine. Debenzylation and subsequently silylation using 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane afforded a bicyclic intermediate which was easily converted into the 2xe2x80x2-thio-LNA analogue upon reaction with potassium thioacetate in DMF and final desilylation (Singh, S. K.; Kumar, R. and Wengel, J., J. Org. Chem., 1998, 63, 6078).
An analogous convergent synthesis of the (1S, 3R, 4R, 7S) -7-hydroxy-1-hydroxymethyl-2,5-dioxabicyclo[2.2.1]heptane thymine using 4-C-tosyloxymethyl-1,2-di-O-acetyl-3,5-di-O-benzyl-D-ribofuranose as the key intermediate for coupling with silylated nucleobases has been reported by the same group (Koshkin, A. A., Rajwanshi, V. K., and Wengel J., Tetrahedron Lett., 1998, 39, 4381).
The use of a 4-C-tosyloxymethyl ribofuranose intermediate has also been suggested by Obika, S. et al (WO 98/39352). In this strategy the 5-O-benzyl protecting group is exchanged for a tert-butyidimethylsilyl protecting group thereby extending the total synthesis of (1S, 3R, 4R, 7S)-7-hydroxy-1-hydroxymethyl-2,5-dioxabicyclo[2.2.1]heptane nucleosides with one step.
Characteristic properties of the previously known strategies discussed above are relatively low overall yields and many synthetic steps. Thus, there is a great need for development of a more efficient synthesis strategy which will result in an improvement of the overall yield and a reduction in the production costs of [2.2.1]bicyclo nucleosides.
The present invention provides a novel strategy for the synthesis of [2.2.1]bicyclic nucleosides comprising the synthesis of a novel key intermediate. The novel strategy is demonstrated by the synthesis of (1S, 3R, 4R, 7S)-7-hydroxy-1-hydroxymethyl-(thymin-1-yl)-2,5-dioxabicyclo[2.2.1]heptane and has easily been extended to the synthesis of [2.2.1]bicyclo nucleosides containing other nucleobases and can be further extended to other heteroatoms than oxygen in the bicycle, such as amino and thio.
The present invention relates to a method for the synthesis of a novel intermediate of the general formula II: 
wherein
R1 is selected from optionally substituted aryl(C1-6-alkyl), optionally substituted tetrahydropyran-2-yl, optionally substituted arylcarbonyl and optionally substituted aryl;
each of the substituents R2 and R3 is independently selected from hydrogen, optionally substituted C1-6-alkyl, optionally substituted aryl, and optionally substituted aryl(C1-6-alkyl), with the proviso that R2 and R3 are not both hydrogen, or R2 and R3 together designate C3-7-alkylene; and
each of the substituents R4 and R5 independently is Rxe2x80x2SO2Oxe2x80x94 wherein Rxe2x80x2 is selected from optionally substituted alkyl and optionally substituted aryl;
said method comprising the following step:
treatment of a compound (hereinafter termed xe2x80x9cstarting materialxe2x80x9d) of the general formula I: 
wherein
R1 is selected from optionally substituted aryl(C1-6-alkyl), optionally substituted tetrahydropyran-2-yl, optionally substituted arylcarbonyl and optionally substituted aryl;
each of the substituents R2 and R3 is independently selected from hydrogen, optionally substituted C1-6-alkyl, optionally substituted aryl, and optionally substituted aryl(C1-6-alkyl), with the proviso that R2 and R3 are not both hydrogen, or R2 and R3 together designate C3-7-alkylene; and
with Rxe2x80x2SO2X wherein Rxe2x80x2 is selected from optionally substituted C1-6-alkyl and optionally substituted aryl, and X designates halogen.
The present invention also relates to the compound of the general formula II as defined above.
The present invention furthermore relates to the compound (hereinafter termed xe2x80x9ckey intermediatexe2x80x9d) of the general formula III: 
wherein
R1 is selected from optionally substituted aryl(C1-6alkyl), optionally substituted tetrahydropyran-2-yl, optionally substituted arylcarbonyl and optionally substituted aryl;
each of the substituents R4 and R5 independently is Rxe2x80x2SO2Oxe2x80x94 wherein Rxe2x80x2 is selected from optionally substituted alkyl and optionally substituted aryl;
R6 is selected from hydrogen, optionally substituted (C1-6-alkyl)carbonyl, optionally substituted arylcarbonyl, optionally substituted aryl(C1-6-alkyl), optionally substituted C1-6-alkyl, and tri(alkyl/aryl)silyl; and
R7 is selected from optionally substituted (C1-6-alkyl)carbonyloxy, optionally substituted C1-6-alkoxy, halogen, optionally substituted arylthio, optionally substituted C1-6-alkylthio, and optionally substituted aryloxy.
The main advantages of the present invention comprise the following:
Obtaining the key intermediate of the general formula II ready for coupling with silylated nucleobases in very few steps from 3-O-benzyl-4-C-hydroxymethyl-1,2-O-isopropylidene-xcex1-D-ribofuranose.
One-pot base-induced ring-closure and desulfonation of the formed [2.2.1]bicyclo nucleoside.
The possibility of using the 5xe2x80x2-sulfonated ring-closed intermediate (compound 5a in example 4) for synthesis of 5xe2x80x2-amino- and thio-LNA.
In an attempt to improve the synthesis of [2.2.1]bicyclo nucleosides, a novel key intermediate for coupling with different nucleobases was synthesised. Using this novel synthesis strategy comprising the novel key intermediate of the general formula III, (1S, 3R, 4R, 7S)-7-hydroxy-1-hydroxymethyl-(thymin-1-yl)-2,5-dioxabicyclo [2.2.1]heptane was synthesised in only five steps from 3-O-benzyl4-C-hydroxymethyl-1,2-0-isopropylidene-xcex1-D-ribofuranose, which makes the novel strategy at least two synthetic step shorter than any previously known strategy. The reduction in numbers of synthetic steps as well as the fact that no chromatographic separation of isomers and fewer deprotection steps are required makes the novel synthesis more convenient and much more cost efficient than previously known strategies. This novel synthesis strategy comprising the novel key intermediate of the general formula III also provided surprisingly facile access to [2.2.1]bicyclo nucleosides comprising other nucleobases and to intermediates which are amenable to oligomerization.
The present invention relates to a method for the synthesis of a novel intermediate with the general formula II: 
wherein
R1 is selected from optionally substituted aryl(C1-6- alkyl), optionally substituted tetrahydropyran-2-yl, optionally substituted arylcarbonyl and optionally substituted aryl. Some preferred embodiments comprise benzyl, o-, m-, and p-methylbenzyl, 2-chlorobenzyl, 4-phenylbenzyl, tetrahydropyran-2-yl, benzoyl, phenyl, among which benzyl and 4-phenylbenzyl are preferred; and
each of the substituents R2 and R3 independently is selected from hydrogen, optionally substituted C1-6-alkyl, optionally substituted aryl, and optionally substituted aryl(C1-6-alkyl), with the proviso that R2 and R3 are not both hydrogen, such as methyl, trifluoromethyl, ethyl, propyl, iso-propyl, butyl, t-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, phenyl, benzyl, phenylethyl, o-, m-, and p-methylbenzyl, 2-chlorobenzyl, or R2 and R3 together designate C3-7-alkylene, such as 1,3-propylene, 1,4-butylene, 1,5-pentylene; and
each of the substituents R4 and R5 independently is Rxe2x80x2SO2Oxe2x80x94, wherein Rxe2x80x2 is selected from optionally substituted C1-6-alkyl, optionally substituted aryl, and optionally substituted aryl(C1-6-alkyl), such as methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, propyl, iso-propyl, butyl, nonafluorobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl, o-, m- or p-methylbenzyl, 2-chlorobenzyl, phenyl, o-, m- or p-bromophenyl, and p-nitrophenyl.
In a preferred embodiment of the invention, the substituents R2 and R3 independently represent hydrogen, methyl, phenyl, benzyl, phenylethyl, preferably methyl.
In an even more preferred embodiment of the invention, the substituents R2 and R3 both represent methyl.
In another embodiment of the invention, each of the substituents R4 and R5 represent methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, 2,2,2-trifluoroethanesulfonyl, propanesulfonyl, iso-propanesulfonyl, butanesulfonyl, nonafluorobutanesulfonyl, pentanesulfonyl, cyclopentanesulfonyl, hexanesulfonyl, cyclohexanesulfonyl, xcex1-toluenesulfonyl, 2-chloro-xcex1-toluenesulfonyl, o-, m-, p-toluenesulfonyl, benzenesulfonyl, o-, m-, p-bromobenzenesulfonyl, and o-, m-, p-nitrobenzenesulfonyl, preferably methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl and p-bromobenzenesulfonyl, more preferably methanesulfonyl, and p-toluenesulfonyl, even more preferably methanesulfonyl.
In a preferred embodiment of the invention, R4 and R5 represent methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, 2,2,2-trifluoroethanesulfonyl, butanesulfonyl, nonafluorobutanesulfonyl, xcex1-toluenesulfonyl, p-toluenesulfonyl, benzenesulfonyl, p-bromobenzenesulfonyl, and p-nitrobenzenesulfonyl, preferably methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl and p-bromobenzenesulfonyl, more preferably methanesulfonyl, and p-toluenesulfonyl, even more preferably methanesulfonyl.
In an especially preferred embodiment of the invention, R4 and R5 are identical and are selected from methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, 2,2,2-trifluoroethanesulfonyl, butanesulfonyl, nonafluorobutanesulfonyl, xcex1-toluenesulfonyl, p-toluenesulfonyl, benzenesulfonyl, p-bromobenzenesulfonyl, and p-nitrobenzene-sulfonyl, preferably methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl and p-bromobenzenesulfonyl, more preferably methanesulfonyl, and p-toluenesulfonyl, even more preferably methanesulfonyl.
Said method comprising the following step:
treatment of a compound with the general formula I: 
wherein
R1, R2 and R3 are as defined above;
with Rxe2x80x2SO2X (hereinafter xe2x80x9csulfonyl halide(s)xe2x80x9d) wherein Rxe2x80x2 is selected from optionally substituted C1-6-alkyl, optionally substituted aryl, and optionally substituted aryl(C1-6-alkyl), such as methyl, trifluoromethyl, ethyl, 2,2,2-trifluproethyl, propyl, iso-propyl, butyl, nonafluorobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl, o-, m- or p-methylbenzyl, 2-chlorobenzyl, phenyl, o-, m- or p-bromophenyl, p-nitrophenyl, and X designates halogen, such as fluoro, chloro, bromo, and iodo.
In a preferred embodiment of the invention, R1 represent benzyl.
In another preferred embodiment of the invention, R2 and R3 is selected from methyl, ethyl, propyl, iso-propyl, benzyl, phenylethyl, phenyl, or R2 and R3 together designate 1,3-propylene, 1,4-butylene, and 1,5-pentylene.
In a more preferred embodiment of the invention, R2 and R3 both represent methyl.
In an especially preferred embodiment of the invention, R1 represent benzyl and R2 and R3 both represent methyl.
In a preferred embodiment of the invention, Rxe2x80x2SO2X represents sulfonyl halides, such as methanesulfonyl chloride, trifluoromethanesulfonyl chloride, ethanesulfonyl chloride, 2,2,2-trifluoroethanesulfonyl chloride, propanesulfonyl chloride, iso-propanesulfonyl chloride, butanesulfonyl chloride, nonafluorobutanesulfonyl chloride, cyclopentanesulfonyl chloride, hexanesulfonyl chloride, cyclohexanesulfonyl chloride, xcex1-toluenesulfonyl chloride, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, preferably methanesulfonyl chloride, trifluoromethanesulfonyl chloride, ethanesulfonyl chloride, 2,2,2-trifluoroethanesulfonyl chloride, nonafluorobutanesulfonyl chloride, xcex1-toluenesulfonyl chloride, p-toluenesulfonyl chloride, even more preferably methanesulfonyl chloride.
The ratio between compound I and sulfonyl halide is typically in the range of 1:2 to 1:10, such as 1:2-1:5, preferably 1:2-1:4, more preferably 1:2.5-1:3.5.
In one embodiment of the invention, compound I may be treated with two different sulfonyl halides, RIIISO2X and RIVSO2X, wherein RIII and RIV are independently selected from the group of substituents defined for Rxe2x80x2 provided that RIII and RIV do not represent the same group, and X is as defined above.
It should be understood that treatment of compound I with RIIISO2X and RIVSO2X is performed in two separate steps. First, compound I is treated with RIIISO2X in the ratio 1:1-1:1.5, preferably 1:1-1:1.3, more preferably 1:1.1-1:1.2, to afford compound II, wherein R4 or R5 is RIIISO2Oxe2x80x94 and R5 or R4 is hydroxyl. Subsequently, the formed compound II is treated with RIVSO2X in the ratio 1:1-1:2.5, preferably 1:1-1:2, more preferably 1:1.1-1:1.5 to afford compound II wherein R4 is RIIISO2Oxe2x80x94 or RIVSO2Oxe2x80x94 and R5 is RIVSO2Oxe2x80x94 if R4 is RIIISO2Oxe2x80x94 and R5 is RIIISO2Oxe2x80x94 and if R4 is RIVSO2Oxe2x80x94.
It should be understood that reaction of compound I with the sulfonyl halide in the presence of an anhydrous base, such as pyridine, 4-dimethylaminopyridine, imidazole, triethylamine, or sodium hydride, increase the overall yield of the reaction.
In a preferred embodiment of the invention, the treatment is performed in the presence of pyridine, imidazole, or 4-dimethylaminopyridine, preferably pyridine.
It should be clear to a person skilled in the art that other sulfonation reagents than sulfonyl halides can be used in the reaction, such as sulfonic acids and anhydrides.
For a person skilled in the art, it should also be clear that the treatment of compound I with the sulfonyl halide typically is carried out in the presence of a solvent, such as pyridine, tetrahydrofuran, toluene, xylene, benzene, ether, ethylacetate, acetonitril, triethylamine, N,N-dimethylformamide, dimethylsulfoxide, dichloromethane, and 1,2-dichloroethane.
For a person skilled in the art, it should likewise be clear that the base and the solvent may be constituted by the same substance, such as pyridine.
The treatment of compound I with sulfonyl halide is typically performed at xe2x88x9270xc2x0 C. to 40xc2x0 C., such as xe2x88x9230xc2x0 C. to 40xc2x0 C.
In a preferred embodiment of the invention, compound I is treated with sulfonyl halide at xe2x88x925xc2x0 C. to 30xc2x0 C., preferably 0xc2x0 C. to 25xc2x0 C.
The present invention also relates to the compound of the general formula II as defined above.
The present invention furthermore relates to the compound of the general formula III: 
wherein
R1, R4, and R5 are as defined above; and
R6 is selected from hydrogen, optionally substituted (C1-6-alkyl)carbonyl, optionally substituted arylcarbonyl, optionally substituted aryl(C1-6-alkyl), optionally substituted C1-6-alkyl, and tri-(alkyl/aryl)silyl, such as acetyl, benzoyl, m-trifluoromethylbenzoyl, benzyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl; and
R7 is selected from optionally substituted (C1-6-alkyl)carbonyloxy, optionally substituted C1-6-alkoxy, halogen, optionally substituted arylthio, optionally substituted C1-6-alkylthio, and optionally substituted aryloxy, such as acetyloxy, methoxy, ethoxy, chloride, fluoride, bromide or iodide, or xe2x80x94SC6H5.
In a preferred embodiment of the invention R1 represents benzyl or 4-phenylbenzyl, most preferably 4-phenylbenzyl, and R4 and R5 both are selected from methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, 2,2,2-trifluoroethanesulfonyl, butanesulfonyl, nonafluorobutanesulfonyl, xcex1-toluenesulfonyl, p-toluenesulfonyl, benzenesulfonyl, p-bromobenzenesulfonyl, and p-nitrobenzenesulfonyl, preferably from methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl and p-bromobenzenesulfonyl, more preferably methanesulfonyl, and p-toluenesulfonyl, even more preferably methanesulfonyl.
In a preferred embodiment of the invention R6 is selected from acetyl, benzoyl and m-trifluoromethylbenzoyl, preferably acetyl, and R7 is selected from acetyloxy, methoxy, ethoxy, chloride, fluroride, bromide, iodide and xe2x80x94SC6H5, preferably acetyloxy and methoxy, even more preferably acetyloxy.
In the most preferred embodiment of the invention R1 represents benzyl or 4-phenylbenzyl, R4 and R5 both represent methanesulfonyl, R6 represents acetyl, and R7 represents acetyloxy.
The key intermediate with the general formula III may be coupled with suitable protected nucleobases resulting in the formation of nucleosides which undergo base-induced ring-closure to afford 2xe2x80x2-O,4xe2x80x2-C-methylene bicyclonucleosides. It should be understood that the formed nucleosides likewise can undergo ring-closure in the presence of different amines, preferably benzylamine, and potassium thioacetate to afford the 2xe2x80x2-N,4xe2x80x2-C-methylene- and 2xe2x80x2-S,4xe2x80x2-C-methylene analogues, respectively.
Compounds with the general formula III may be obtained from compound II by one of the following strategies:
treatment of compound II with 80% acetic acid or trifluoroacetic acid followed by treatment of the formed intermediate with acetic anhydride (a corresponding longer chain acid anhydride) in pyridine afford compound III wherein R6 is acetyl and R7 is acetyloxy;
treatment of compound II with HCl in methanol (or a longer chain alcohol) afford compound III wherein R6 is hydrogen and R7 is methoxy (or a longer chain alkoxy). The formed compound III can be further transformed to obtain compounds of the formula III where in R6 is as defined above;
treatment of compound II with HCl in methanol afford compound III wherein R6 is hydrogen and R7 is methoxy. Transformation of R6 into one of the groups described above followed by treatment of the formed product with HCl(g) in dichloromethane afford compound III wherein R7 is chloro and R6 is as defined above;
conversion of compound II into compound III wherein R7 is C6H5Sxe2x80x94 is performed as described in the literature.
Synthesis of [2.2.1]bicyclo Nucleosides
As an illustrative example of synthesis of [2.2.l]bicyclo nucleosides using the method of the present invention (1S, 3R, 4R, 7S)-7-hydroxy-1-hydroxymethyl-(thymin-1-yl)-2,5-dioxabicyclo[2.2.1]heptane (7) was synthesized using 3-O-benzyl-4-C-hydroxymethyl-1,2-O-isopropylidene-xcex1-D-ribofuranose (1) as starting material (FIGS. 1 and 3). Methanesulfonyl chloride (2.7 equivalents) was added to 1 (1 equivalent) in dry pyridine at 0xc2x0 C. and the reaction mixture was allowed to heat to room temperature. The reaction mixture was stirred for 1 hour at room temperature affording the key intermediate 2 in 98% yield after aqueous work up. Compound 2 was used in the following step with out further purification. Subsequent, acetolysis of the intermediate 2 using 80% trifluoroacetic acid followed by acetylation with acetic acid (3 equivalents) in pyridine afforded the key intermediate 3 in 92% yield. Compound 3 was coupled with silylated nucleobase using trimethylsilyl trifluoromethanesulfonate as a Lewis acid according to the methodology developed by Vorbruggen H (Vorbruggen, K.; Krolikiewicz, K. and Bennua B., Chem. Ber. 114, 1234-1255, (1981). Purification by silica gel flash chromatography afforded the nucleoside 4 in 85% yield. Direct based-induced ring-closure was performed by treating compound 4 with 0.5 M NaOH (1,4-dioxane:H2O, 1:1) and refluxed overnight. Aqueous work-up and purification by silica gel flash chromatography afforded compound 6 in 88% yield. Catalytic hydrogenation afforded (1S, 3R, 4R, 7S)-7-hydroxy-1-hydroxymethyl-(thymin-1-yl)-2,5-dioxabicyclo[2.2.1]heptane (7) in 84% yield after crystallisation from 10% ethanol in dichloromethane.
Synthesis of (1S, 3R, 4R, 7S) -7-hydroxy-1-hydroxymethyl-(guanin-9-yl)-2,5-dioxabicyclo[2.2.]heptane was performed using the same strategy. Guanidine derivatives were also prepared by a similar strategy, such as the (1S,3R,4R,7S)-7-hydroxy-1-hydroxymethyl-3-(2-N-isobutyrylguanin-9-yl)-2,5-dioxabicyclo[2.2.1]heptane 16, as illustrated by FIG. 2.
The advantageous versatility of a strategy according to this invention, wherein the key intermediate (compounds of general formula III) is employed, is further illustrated by the fact that isomers with C2xe2x80x2 (nucleoside numbering) inversion are accessible to give xcex1-L-ribose sugars. Thus, the thymidinyl-xcex1-L-ribose 12 was prepared from the key intermediate. This preparation xcex1-L-ribose [2.2.1]bicyclo nucleosides from the key intermediate has been applicable to other naturally occurring and non-naturally occurring nucleobases.
The versatility of this route is further illustrated in FIGS. 4 to 8 wherein [2.2.1]bicyclo nucleoside derivatives of adenosine, cytosine, uridine, thymidine and guanidine are accessible from the key intermediate of the general formula III. FIG. 6 illustrates a combination of preferred embodiments for compounds the general formula III for the preparation of [2.2.l]bicyclo nucleoside derivatives of uridine, wherein R7 is acetoxy, R4 and R5 are each mesylate and R1 is the aryl substituted benzyl, phenylbenzyl (labelled compound 106 in FIG. 6).